The proposed research aims to study the role of putative cell death genes [encoding interleukin-1 beta converting enzyme (ICE), mICE2, and Nedd-2] in normal mouse development and in tumorigenesis. The importance of these genes derives from the fact that they have homology to the C. elegans cell death gene ced-3.The proposed experiments test whether these genes function similarly to ced-3 in mammalian cells. Specifically, Dr. Yuan will 1) isolate genomic clones and construct gene-targeting vector to disrupt gene activity, 2) establish ES cell cultures and transgenic mice with these disrupted genes, 3) characterize the developmental phenotypes of these transgenic mice, 4) determine if the mutations are tumorigenic in the animals, and 5) study tumorigenesis in cell lines derived from the mouse strains.